First-in-class neuroprotective therapy in acute ischemic stroke, poststroke cognitive impairment and mechanistically related diseases by network pharmacology of common signalling targets

• Applicant: Dr. Ana I. Casas Guijarro
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Experimental Models for the Understanding of Nervous System Diseases ; Pharmacology
• Term: from 2020 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 449729893

Stroke currently represents one of the highest unmet medical needs. Despite being the primary cause of disability and fifth of mortality, only one single drug is currently approved. However, more than 30 associated contraindications leaves 85% of all stroke patients without any pharmacotherapy. I identified oxidative and nitrative stress and their interaction as a major cause of brain damage post-stroke. In fact, I validated three independent targets: NADPH oxidase, NO synthase and the cGMP forming enzyme, sGC; which could be safely modulated by NOX inhibitors, NOS inhibitors and sGC activators, respectively. Despite their neuroprotective effect, all single target approaches in stroke failed during the last decades. To overcome this recurrent “one-target, one-drug” therapeutic failure, I propose a novel strategy so-called network pharmacology. This approach focusses on mechanistically-related, synergistic targets achieving both maximal efficacy and safety. Thus, I will acutely examine several synergies focusing on combinatory approaches establishing therapeutic synergy as the ultimate goal. However, treating acute stroke remains insufficient. Importantly, 30% of stroke patients experience residual cognitive impairment. Therefore, I will adapt an already validated acute network pharmacology therapy to a new chronic frame focused on post-stroke cognitive impairment. However, the ROS-cGMP signaling network is also impaired in other non-treatable mechanism-related cognitive disorders, i.e. vascular dementia. Additionally, neither patient stratification or predictive prognosis through biomarkers are nowadays possible since all possible candidates are not sufficiently specific. Therefore, I suggest to expand my work on acute stroke therapy and network pharmacology to different neurovascular and cognitive impaired scenarios in order to translate the first broadly applicable, safe, effective and neuroprotective therapy from acute brain ischemia to post-stroke cognitive impairment and vascular dementia together with a potent biomarker identification strategy.

• DFG Programme: WBP Position